Building confidence in mechanistic evidence derived from high throughput assay data in ToxCast to inform hazard evaluation

Mechanistic evidence can play a critical role in hazard evaluation in human health risk assessment. New approach methodologies (NAMs) can rapidly provide mechanistic data in support of weight of evidence (WoE). While NAMs have provided valuable evidence in support of hazards such as skin sensitization, their applicability for developmental and reproductive hazards has yet to be fully interrogated. The Key Characteristics (KCs) approach provides a systematic method for identifying, organizing, and synthesizing mechanistic evidence. When used in tandem with the mode of action (MOA) framework, the KCs approach can help facilitate informing key event relationships using mechanistic evidence for a given toxicant and hazard. Previously assessed chemicals with existing MOAs for a given hazard can be used to validate and build confidence in using the KCs approach to organize and integrate mechanistic and NAM-based data into an MOA. However, the extent to which existing NAM-based mechanistic evidence can be integrated into this type of evidence stream or how well NAMs data covers this biological space is not well characterized for developmental and reproductive toxicants. In order to build scientific confidence in the use of NAMs to inform mechanistic evaluations in support of hazard characterization, a critical next step requires interrogation of the reliability and relevance of NAMs and determining how these data can be integrated into mechanistic data derived from in vivo studies to support weight of evidence in the context of MOA development. The objectives of this project are to: (1) determine the extent to which the key characteristics of male and female reproductive toxicants are informed by currently available in vitro bioactivity data from the ToxCast/Tox21 database, using several established reproductive toxicants as case studies, (2) leverage an existing case study using the KCs of male reproductive toxicants to organize the mechanistic evidence for a well-studied and well characterized chemical (e.g. benzo[a]pyrene, dibutyl phthalate, etc) to further explore integration of ToxCast/Tox21 NAMs data into evidence streams such as MOA analysis, (3) interrogate the extent to which NAMs data in ToxCast/Tox21 support weight of evidence evaluation for developmental neurotoxicity, using an evidence-rich chemical as a case study This work will increase confidence in the application of NAM data by demonstrating ways to integrate the information into existing lines of evidence that inform reproductive toxicity and developmental neurotoxicity mechanisms while identifying data gaps to guide the development/inclusion of new assays.

Impact/Purpose

Mechanistic evidence can play a critical role in hazard evaluation in human health risk assessment. New approach methodologies (NAMs) can rapidly provide mechanistic data in support of weight of evidence (WoE). While NAMs have provided valuable evidence in support of hazards such as skin sensitization, their applicability for developmental and reproductive hazards has yet to be fully interrogated. The Key Characteristics (KCs) approach provides a systematic method for identifying, organizing, and synthesizing mechanistic evidence. When used in tandem with the mode of action (MOA) framework, the KCs approach can help facilitate informing key event relationships using mechanistic evidence for a given toxicant and hazard. Previously assessed chemicals with existing MOAs for a given hazard can be used to validate and build confidence in using the KCs approach to organize and integrate mechanistic and NAM-based data into an MOA. However, the extent to which existing NAM-based mechanistic evidence can be integrated into this type of evidence stream or how well NAMs data covers this biological space is not well characterized for developmental and reproductive toxicants. In order to build scientific confidence in the use of NAMs to inform mechanistic evaluations in support of hazard characterization, a critical next step requires interrogation of the reliability and relevance of NAMs and determining how these data can be integrated into mechanistic data derived from in vivo studies to support weight of evidence in the context of MOA development. The objectives of this project are to: (1) determine the extent to which the key characteristics of male and female reproductive toxicants are informed by currently available in vitro bioactivity data from the ToxCast/Tox21 database, using several established reproductive toxicants as case studies, (2) leverage an existing case study using the KCs of male reproductive toxicants to organize the mechanistic evidence for a well-studied and well characterized chemical (e.g. benzo[a]pyrene, dibutyl phthalate, etc) to further explore integration of ToxCast/Tox21 NAMs data into evidence streams such as MOA analysis, (3) interrogate the extent to which NAMs data in ToxCast/Tox21 support weight of evidence evaluation for developmental neurotoxicity, using an evidence-rich chemical as a case study This work will increase confidence in the application of NAM data by demonstrating ways to integrate the information into existing lines of evidence that inform reproductive toxicity and developmental neurotoxicity mechanisms while identifying data gaps to guide the development/inclusion of new assays.

Citation

Blake, B., T. Anderson, X. Arzuaga Andino, AND I. Druwe. Building confidence in mechanistic evidence derived from high throughput assay data in ToxCast to inform hazard evaluation. Systematic Review Community of Practice Meeeting, Durham, NC, July 11, 2023.

• KCS_NAMS_TRAC_2023-FINAL.PPTX
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